Abstract
The purpose of this study was to determine the relationship between methylation status of the Dact1 gene and MTHFR a1298c polymorphic forms in transitional cell carcinoma tissues in a Chinese population. Polymorphisms of folate metabolism enzyme gene MTHFR were assessed by restrictive fragment length polymorphism (RFLP) methods and PCR-based DNA methylation analysis was used to determine the CpG island methylation status of the Dact1 gene. Associations between the methylation status of the Dact1 gene and clinical characteristics, as well as MTHFR a1298c polymorphisms, were analyzed. aberrant methylation of the Dact1 gene was found in 68.3% of cancer tissues and 12.4% of normal tissues,. The methylation rate of the Dact1 gene in cancer tissues was significantly higher in patients with lymph node metastasis than in those without lymph node metastasis (46.3% vs. 17.2%, P = 0.018). No association was found between aberrant DNA methylation and selected factors including sex, age, tobacco smoking, alcohol consumption and green tea consumption. After adjusting for potential confounding variables, variant allele of MTHFR a1298c was found to be associated with methylation of the Dact1 gene. Compared with wild type CC, the odds ratio was 4.33 (95% CI: 1.06-10.59) for AC and 4.95 (95% CI: 1.18-12.74) for AA. The N stage in TNM staging and the occurrence of lymph node metastasis were associated with an MTHFR 1298 AAμAC genotype (P<0.05). MTHFR 1298 AC and AA genotypes might help maintain a normal methylation status of the Dact1 gene, aberrant CpG island methylation of which is closely related to the genesis and progression of transitional cell carcinoma.
Highlights
500,000 individuals suffered from bladder cancer in the U.S (Marsit et al, 2010), transitional cell carcinoma (TCC) of the bladder cancer is one of the most common malignancies affecting the genitourinary tract and is characterized by multifocality and a high incidence of recurrence (Vikram et al, 2009)
Polymorphisms of folate metabolism enzyme gene Methylenetetrahydrofolate reductase (MTHFR) were assessed by restrictive fragment length polymorphism (RFLP) methods and PCR-based DNA methylation analysis was used to determine the CpG island methylation status of the Dact1 gene
The methylation rate of the Dact1 gene in cancer tissues was significantly higher in patients with lymph node metastasis than in those without lymph node metastasis (46.3% vs. 17.2%, P = 0.018)
Summary
500,000 individuals suffered from bladder cancer in the U.S (Marsit et al, 2010) , transitional cell carcinoma (TCC) of the bladder cancer is one of the most common malignancies affecting the genitourinary tract and is characterized by multifocality and a high incidence of recurrence (Vikram et al, 2009). The carcinogenesis process is unclear so far, accumulation of multiple genetic and epigenetic alternations leading to the activation of proto-oncogenes and/or inactivation of tumor-suppressor genes (TSGs) is a common consensus (Hansen and Cavenee, 1988; Hunter, 1997; Jones and Baylin, 2007). Aberrant DNA methylation is recognized as an important epigenetic alteration occurring early in human cancers (Fang et al, 2006), involving bladder cancer (Tada et al, 2011). DNA methylation alterations are probably the most widely studied epigenetic alterations in cancer (Brait and Sidransky, 2011), and plays a strong role in tumorigenesis (Eze et al, 2011), which increasingly becoming a hot research area. One study done in Espana demonstrated that neoplasia is correlated with overall genomic hypomethylation (Gonzalo et al, 2008), failure to repress genes appropriately by abnormal demethylation of tissue-restricted genes or by hypomethylation of proto-oncogenes could result in the loss of tissue specificity and could promote cancer formation
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